U.S. patent application number 14/127231 was filed with the patent office on 2014-08-07 for process.
This patent application is currently assigned to BIAL-PORTELA & CA, S.A.. The applicant listed for this patent is Alexander Beliaev, David Alexander Learmonth, Jonathan Madec, William Maton, Jean-Marie Schneider, Jorge Bruno Reis Wahnon. Invention is credited to Alexander Beliaev, David Alexander Learmonth, Jonathan Madec, William Maton, Jean-Marie Schneider, Jorge Bruno Reis Wahnon.
Application Number | 20140221668 14/127231 |
Document ID | / |
Family ID | 46551833 |
Filed Date | 2014-08-07 |
United States Patent
Application |
20140221668 |
Kind Code |
A1 |
Beliaev; Alexander ; et
al. |
August 7, 2014 |
Process
Abstract
The present invention relates to a process for preparing
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione, and pharmaceutically acceptable salts thereof,
especially the hydrochloride salt. The invention also relates to a
process for making intermediates useful in the formation of said
compound, and to the intermediates, per se.
Inventors: |
Beliaev; Alexander; (S.
Mamede do Coronado, PT) ; Wahnon; Jorge Bruno Reis;
(S. Mamede do Coronado, PT) ; Learmonth; David
Alexander; (Alfena, PT) ; Madec; Jonathan;
(Chatou, FR) ; Schneider; Jean-Marie;
(Magnanville, FR) ; Maton; William; (S. Mamede do
Coronado, PT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Beliaev; Alexander
Wahnon; Jorge Bruno Reis
Learmonth; David Alexander
Madec; Jonathan
Schneider; Jean-Marie
Maton; William |
S. Mamede do Coronado
S. Mamede do Coronado
Alfena
Chatou
Magnanville
S. Mamede do Coronado |
|
PT
PT
PT
FR
FR
PT |
|
|
Assignee: |
BIAL-PORTELA & CA, S.A.
S. Mamede do Coronado
PT
|
Family ID: |
46551833 |
Appl. No.: |
14/127231 |
Filed: |
June 29, 2012 |
PCT Filed: |
June 29, 2012 |
PCT NO: |
PCT/PT2012/000024 |
371 Date: |
April 7, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61502647 |
Jun 29, 2011 |
|
|
|
Current U.S.
Class: |
548/311.4 ;
560/253; 564/200; 564/87 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 9/00 20180101; C07C 235/80 20130101; C07C 311/17 20130101;
A61P 9/04 20180101; C07C 311/16 20130101; C07D 405/04 20130101 |
Class at
Publication: |
548/311.4 ;
564/200; 564/87; 560/253 |
International
Class: |
C07D 405/04 20060101
C07D405/04; C07C 311/17 20060101 C07C311/17; C07C 235/80 20060101
C07C235/80 |
Claims
1. A process for preparing a compound of formula RY or a
pharmaceutically acceptable salt thereof, ##STR00039## wherein,
R.sub.1, R.sub.2 and R.sub.3 are the same or different and signify
hydrogen, halogen, alkyl, nitro, amino, alkylcarbonylamino,
alkylamino or dialkylamino group; and X signifies CH.sub.2, an
oxygen atom or a sulphur atom; which process comprises deprotecting
a compound of formula K ##STR00040## wherein R.sub.1, R.sub.2,
R.sub.3 and X are as hereinbefore defined in formula RY and Ns
signifies o-nitrophenylsulphonyl; and optionally thereafter
converting the compound RY to a pharmaceutically acceptable salt
thereof.
2-3. (canceled)
4. A process according to claim 1, wherein compound RY has the
formula RY' ##STR00041##
5. A process according to claim 1, wherein said deprotection step
comprises treating a compound of formula K with thioglycolic acid
in a suitable solvent, in the presence of a base, preferably LiOH
or KOH.
6. A process according to claim 1, wherein the compound RY isolated
from the deprotection step is purified.
7. A process according to claim 6, wherein purification is
performed: via a two-step procedure comprising (i) formation of an
HCl salt of a compound of formula RY and (ii) crystallisation of
the HCl salt so formed from a suitable solvent, preferably toluene;
or via a re-slurry in 2-butanone.
8. A process according to claim 1, wherein the compound of formula
K is prepared by reacting a compound of formula I, ##STR00042##
wherein Ns signifies o-nitrophenylsulphonyl; with a compound of
formula JZ, ##STR00043## wherein R.sub.1, R.sub.2, R.sub.3 are the
same or different and signify hydrogen, halogen, alkyl, nitro,
amino, alkylcarbonylamino, alkylamino or dialkylamino group, X
signifies CH.sub.2, an oxygen atom or a sulphur atom, and Z is
selected from L-tartrate, hydrochloride, mesylate, tosylate,
trifluotoacetate, citrate, glycolate and oxalate.
9-19. (canceled)
20. A process for preparing a compound of formula RY or a
pharmaceutically acceptable salt thereof according to claim 1, the
process comprising converting benzylamine E to a compound of
formula F in the presence of o-nitrophenylsulphonyl chloride and
methyl vinyl ketone (MVK); brominating the compound F to a compound
of formula G; hydroxylation of compound G to a compound of formula
I or acetylating compound G to form a compound of formula H
followed by hydrolysing the compound H to form a compound of
formula I; reacting the compound I with a compound of formula J to
form a compound of formula K; and deprotecting compound K to form
compound RY, and optionally converting compound RY to a
pharmaceutically acceptable salt thereof, ##STR00044## wherein Ns
is o-nitrophenylsulphonyl, and R.sub.1, R.sub.2, R.sub.3 are the
same or different and signify hydrogen, halogen, alkyl, nitro,
amino, alkylcarbonylamino, alkylamino or dialkylamino group and X
signifies CH.sub.2, an oxygen atom or a sulphur atom.
21. A process for preparing a compound of formula RY or a
pharmaceutically acceptable salt thereof, ##STR00045## wherein,
R.sub.1, R.sub.2 and R.sub.3 are the same or different and signify
hydrogen, halogen, alkyl, nitro, amino, alkylcarbonylamino,
alkylamino or dialkylamino group; and X signifies CH.sub.2, an
oxygen atom or a sulphur atom; which process comprises reducing a
compound of formula D, ##STR00046## wherein R.sub.1, R.sub.2,
R.sub.3 and X are as hereinbefore defined in formula RY; and
optionally thereafter converting the compound RY to a
pharmaceutically acceptable salt thereof.
22-23. (canceled)
24. A process according to claim 21, wherein compound RY has the
formula RY' ##STR00047##
25. A process according to claim 21, wherein the reduction of
compound D to the compound RY is carried out using a reducing agent
comprising a NaBH.sub.4--BF.sub.3. complex.
26. A process according to claim 25, wherein the
NaBH.sub.4--BF.sub.3. complex is NaBH.sub.4--BF.sub.3.THF.
27. A process according to claim 21, wherein the compound of
formula D is prepared by condensing a compound of formula C,
##STR00048## with a compound of formula JT, ##STR00049## wherein
R.sub.1, R.sub.2, R.sub.3 are the same or different and signify
hydrogen, alkyl, nitro, amino, alkylcarbonylamino, alkylamino or
dialkylamino group, and X signifies CH.sub.2, an oxygen atom or a
sulphur atom.
28-34. (canceled)
35. A process for preparing a compound of formula RY or a
pharmaceutically acceptable salt thereof according to claim 21, the
process comprising: brominating a compound of formula A to form a
compound of formula B; hydroxylation of compound B to the compound
of formula C; cyclising the compound C to form the compound of
formula D; and reducing the compound D to form the compound of
formula RY, and optionally converting compound RY to a
pharmaceutically acceptable salt thereof ##STR00050## wherein
R.sub.1, R.sub.2, R.sub.3 are the same or different and signify
hydrogen, halogen, alkyl, nitro, amino, alkylcarbonylamino,
alkylamino or dialkylamino group; and X signifies CH.sub.2, an
oxygen atom or a sulphur atom.
36. A process according to claim 1, wherein the process further
comprises converting the compound RY to the HCl salt thereof.
37. (canceled)
38. A compound of formula B or C: ##STR00051## ##STR00052##
39. (canceled)
40. A compound of formula D ##STR00053## where R.sub.1, R.sub.2 and
R.sub.3 are the same or different and signify hydrogen, halogen,
alkyl, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino
group; and X signifies CH.sub.2, an oxygen atom a or sulphur
atom.
41-42. (canceled)
43. A compound according to claim 40, wherein compound D has the
formula D' ##STR00054##
44. A compound of formula F, G, H, or I wherein Ns is
o-nitrophenylsulphonyl: ##STR00055##
45-47. (canceled)
48. A compound of formula K ##STR00056## where Ns is
o-nitrophenylsulphonyl, R.sub.1, R.sub.2 and R.sub.3 are the same
or different and signify hydrogen, halogen, alkyl, nitro, amino,
alkylcarbonylamino, alkylamino or dialkylamino group; and X
signifies CH.sub.2, an oxygen atom or a sulphur atom; wherein the
term alkyl means hydrocarbon chains, straight or branched,
containing from one to six carbon atoms, optionally substituted by
aryl, alkoxy, halogen, alkoxycarbonyl or hydroxycarbonyl groups;
the term aryl means a phenyl or naphthyl group, optionally
substituted by alkyl, alkyloxy, halogen or nitro group; the term
halogen means fluorine, chlorine, bromine or iodine; the term
heteroaryl means heteroaromatic group.
49-50. (canceled)
51. A compound according to claim 48, wherein compound K has the
formula K' ##STR00057##
52-54. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a filing under 35 U.S.C. 371 of
International Application No. PCT/PT2012/000024 filed Jun. 29,
2012, entitled "Process," which claims priority to U.S. Provisional
Patent Application No. 61/502,647 filed Jun. 29, 2011, which
applications are incorporated by reference herein in their
entirety.
FIELD OF INVENTION
[0002] The present invention relates to a process for preparing
.RTM.-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole--
2(3H)-thione, and pharmaceutically acceptable salts thereof,
especially the hydrochloride salt. The invention also relates to a
process for making intermediates useful in the formation of said
compound, and to the intermediates, per se.
BACKGROUND OF THE INVENTION
[0003] In recent years, interest in the development of inhibitors
of dopamine-.beta.-hydroxylase (D.beta.H) has centred on the
hypothesis that inhibition of this enzyme may provide significant
clinical improvements in patients suffering from cardiovascular
disorders such as hypertension or chronic heart failure. The
rationale for the use of D.beta.H inhibitors is based on their
capacity to inhibit the biosynthesis of noradrenaline, which is
achieved via enzymatic hydroxylation of dopamine. Activation of
neurohumoral systems, chiefly the sympathetic nervous system, is
the principal clinical manifestation of congestive heart failure
(Parmley, W. W., Clinical Cardiology, 18: 440-445, 1995).
Congestive heart failure patients have elevated concentrations of
plasma noradrenaline (Levine, T. B. et al., Am. J. Cardiol.,
49:1659-1666, 1982), increased central sympathetic outflow
(Leimbach, W. N. et al., Circulation, 73: 913-919, 1986) and
augmented cardiorenal noradrenaline spillover (Hasking, G. J. et
al., Circulation, 73:615-621, 1966). Prolonged and excessive
exposure of the myocardium to noradrenaline may lead to
down-regulation of cardiac .beta..sub.1-adrenoceptors, remodelling
of the left ventricle, arrhythmias and necrosis, all of which can
diminish the functional integrity of the heart. Congestive heart
failure patients who have high plasma concentrations of
noradrenaline also have the most unfavourable long-term prognosis
(Cohn, J. N. et al., N. Engl. J. Med., 311:819-823, 1984). Of
greater significance is the observation that plasma noradrenaline
concentrations are already elevated in asymptomatic patients with
no overt heart failure and can predict ensuing mortality and
morbidity (Benedict, C. R. et al., Circulation, 94:690-697, 1996).
An activated sympathetic drive is not therefore merely a clinical
marker of congestive heart failure, but may contribute to
progressive worsening of the disease.
[0004] Inhibition of sympathetic nerve function with adrenoceptor
antagonists appeared a promising approach, however a significant
proportion of patients do not tolerate the immediate haemodynamic
deterioration that accompanies p-blocker treatment (Pfeffer, M. A.
et al., N. Engl. J. Med., 334:1396-7, 1996). An alternative
strategy for directly modulating sympathetic nerve function is to
reduce the biosynthesis of noradrenaline via inhibition of
D.beta.H, the enzyme responsible for conversion of dopamine to
noradrenaline in sympathetic nerves. This approach has several
advantages including gradual modulation as opposed to abrupt
inhibition of the sympathetic system, and increased release of
dopamine, which can improve renal function such as renal
vasodilation, diuresis and natriuresis. Therefore, inhibitors of
D.beta.H may provide significant advantages over conventional
.beta.-blockers.
[0005] Several inhibitors of D.beta.H have been thus far reported
in the literature. Early first and second generation examples such
as disulfuram (Goldstein, M. et al., Life Sci., 3:763, 1964) and
diethyldithiocarbamate (Lippmann, W. et al., Biochem. Pharmacol.,
18: 2507, 1969) or fusaric acid (Hidaka, H. Nature, 231, 1971) and
aromatic or alkyl thioureas (Johnson, G. A. et al, J. Pharmacol.
Exp. Ther., 171: 80, 1970) were found to be of low potency,
exhibited poor selectivity for D.beta.H and caused toxic side
effects. The third generation of D.beta.H inhibitors however, were
found to have much greater potency, such as for example, nepicastat
(RS-25560-197, IC.sub.50 9 nM) (Stanley, W. C., et al., Br. J.
Pharmacol., 121: 1803-1809, 1997), which was developed to early
clinical trials. Although devoid of some of the problems associated
with first and second generation D.beta.H inhibitors, a very
important discovery was that nepicastat was found to cross the
blood brain barrier (BBB), and was thereby able to cause central as
well as peripheral effects, a situation which could lead to
undesired and potentially serious CNS side-effects of the drug.
Therefore, there remains an unfulfilled clinical requirement for a
potent, non-toxic and peripherally selective inhibitor of D.beta.H,
which could be used for treatment of certain cardiovascular
disorders. A D.beta.H inhibitor with similar or even greater
potency than nepicastat, but devoid of CNS effects (inability to
cross the BBB) would provide a significant improvement over all
D.beta.H inhibitor compounds thus far described in the prior
art.
[0006] Dopamine-.beta.-hydroxylase inhibitors are also disclosed in
WO95/29165. Furthermore, WO 2004/033447 discloses
dopamine-.beta.-hydroxylase inhibitors having high potency and
significantly reduced brain access, giving rise to potent and
peripherally selective D.beta.H inhibitors.
[0007] WO2008/136695 discloses a compound of formula I:
##STR00001##
where R.sub.1, R.sub.2 and R.sub.3 are the same or different and
signify hydrogens, halogens, alkyl, nitro, amino,
alkylcarbonylamino, alkylamino or dialkylamino group; R.sub.4
signifies -alkylaryl or -alkylheteroaryl; X signifies CH.sub.2,
oxygen atom or sulphur atom; and n is 2 or 3. WO2008/136695 also
discloses a compound of formula Y, its (R) or (S) enantiomer, or
mixture of (R) and (S) enantiomer, or pharmaceutically acceptable
salts or esters thereof.
##STR00002##
SUMMARY OF THE INVENTION
[0008] We have now found new processes for preparing inter alia
compounds of formula Y'.
[0009] The present invention provides processes for preparing a
compound of formula RY', which is the R-enantiomer of compound Y'.
The present invention also relates to derivatives of compound RY',
which derivatives have the formula RY.
##STR00003##
[0010] The present invention also provides intermediates for use in
the processes, and processes for preparing and using the
intermediates.
DETAILED DESCRIPTION OF THE INVENTION
[0011] According to a first aspect of the present invention, there
is provided a process for preparing a compound of formula RY or a
pharmaceutically acceptable salt thereof,
##STR00004##
wherein, R.sub.1, R.sub.2 and R.sub.3 are the same or different and
signify hydrogen, halogen, alkyl, nitro, amino, alkylcarbonylamino,
alkylamino or dialkylamino group; and X signifies CH.sub.2, oxygen
atom or sulphur atom; which process comprises reducing a compound
of formula D,
##STR00005##
wherein R.sub.1, R.sub.2, R.sub.3 and X are as hereinbefore defined
in formula RY; and optionally thereafter converting the compound RY
to a pharmaceutically acceptable salt thereof.
[0012] According to a preferred embodiment of the present
invention, the compound of formula D is prepared by condensing a
compound of formula C,
##STR00006##
with a compound of formula JT,
##STR00007##
wherein R.sub.1, R.sub.2, R.sub.3 and X are as hereinbefore defined
in formula RY.
[0013] According to a further preferred embodiment of the
invention, the compound of formula C is prepared by hydroxylating a
compound of formula B,
##STR00008##
[0014] According to a still further preferred embodiment of the
invention, the compound of formula B is prepared brominating a
compound of formula A,
##STR00009##
[0015] A particularly preferred process for preparing a compound of
formula RY according to the present invention is as shown in Scheme
1.
##STR00010##
The process comprises: brominating a compound of formula A to form
a compound of formula B; hydroxylating a compound B to a compound
of formula C; condensing the compound C with a compound of formula
JT to form a compound of formula D; and reducing the compound D to
form the compound of formula RY, and optionally converting compound
RY to a pharmaceutically acceptable salt thereof; where R.sub.1,
R.sub.2 and R.sub.3 are the same or different and signify hydrogen,
halogen, alkyl, nitro, amino, alkylcarbonylamino, alkylamino or
dialkylamino group; and X signifies CH.sub.2, oxygen atom or
sulphur atom.
[0016] As used herein the term "alkyl" means hydrocarbon chains,
straight or branched, containing from one to six carbon atoms,
optionally substituted by aryl, alkoxy, halogen, alkoxycarbonyl or
hydroxycarbonyl groups.
[0017] As used herein, the term "aryl" means a phenyl or naphthyl
group, optionally substituted by alkyl, alkyloxy, halogen or nitro
group.
[0018] As used herein, the term "halogen" means fluorine, chlorine,
bromine or iodine; the term heteroaryl means heteroaromatic
group.
[0019] In an embodiment, X is O.
[0020] In an embodiment, one of R.sub.1, R.sub.2 and R.sub.3 is
hydrogen, and the others are fluorine.
[0021] In an embodiment, compound RY has the formula RY'
##STR00011##
and the process is as defined in Scheme 1' below.
##STR00012##
[0022] The brominating step is carried out in the presence of a
suitable brominating reagent such as N-bromosuccinimide (NBS),
dibromohydantoin or bromine. In a preferred embodiment, the
brominating step is carried out in the presence of bromine.
Suitably, the bromination is carried out at a temperature ranging
from about 0.degree. C. to about 25.degree. C., preferably from
about 0.degree. C. to about 5.degree. C. Preferably, the reaction
mixture is heated to room temperature, i.e. around 25.degree. C.,
after addition of bromine. It has been observed that the
bromination reaction may result in a mixture of isomers. In such
circumstances, the process may further comprise treating of the
bromination product B (suitably after filtration thereof with DCM)
with a suitable aqueous base such as aqueous bicarbonate solution,
followed by extraction with a suitable solvent such as methyl
tert-butyl ether (MTBE) and crystallization from a further suitable
solvent such as MTBE.
[0023] In an embodiment, the conversion of the bromide B to the
hydroxy ketone C is achieved by treatment with an alkaline metal
formate, preferably sodium, potassium or cesium formate, most
preferably potassium formate in a suitable solvent such as
methanol, preferably boiling methanol. For this step, crude bromide
of formula B may be used without purification (i.e. either as the
HBr salt or as the free base). Advantageously, the hydroxy ketone C
was observed to be obtained as a stable crystalline material.
Preferably, the reaction temperature is about 50.degree. C. or
higher, more preferably from about 50.degree. C. to the reflux
temperature of the solvent used. Most preferably, the reaction is
carried out under reflux.
[0024] When the HBr salt is used for the conversion, the alkaline
metal formate is present in at least 3 molar equivalents. When the
free base is used for the conversion, the alkaline metal formate is
present in at least 2 molar equivalents.
Cyclisation of the hydroxy ketone C with compound JT is preferably
carried out using an alkali metal thiocyanate such as potassium
thiocyanate and a suitable acid such as acetic acid (AcOH) in a
suitable solvent such as 2-propanol. Advantageously, the use of
2-propanol avoids the need for chromatographic purification of
compound D.
[0025] In an embodiment, the reduction of compound D to the target
material compound RY is carried out using a reducing agent
comprising NaBH.sub.4--BF.sub.3. complex such as
NaBH.sub.4--BF.sub.3.Et.sub.2O, NaBH.sub.4--BF.sub.3.THF,
preferably NaBH.sub.4--BF.sub.3.THF in a suitable solvent such as
THF or Me-THF, preferably THF (it is believed that this results in
in situ borane formation). Suitable amounts of reducing agent are 5
or 2.5 molar equivalents of each or 2.5 molar equivalents of
NaBH.sub.4 with 3.3 molar equivalents of BF.sub.3.Et.sub.2O or
BF.sub.3.THF, preferably 2.5 molar equivalents of NaBH.sub.4 with
3.3 molar equivalents of BF.sub.3.THF. Alternative reducing agents
are sodium bis(methoxyethoxy)aluminohydride) (RedAl.TM.),
Borane-THF complex (BTHF) and NaBH.sub.4-methanesulfonic acid.
[0026] In an embodiment, the process further comprises converting
the compound RY to a pharmaceutically acceptable salt thereof.
Suitable pharmaceutically acceptable salts include acid addition
salts. Preferably, the pharmaceutically acceptable salt is the HCl
salt.
[0027] It will be appreciated that several of the intermediates for
use in the process are novel and inventive, as are the processes
for preparing them and the processes involving their use. These
intermediates and processes form further aspects of the present
invention, as is described below.
[0028] According to another aspect of the present invention, there
is provided a compound of formula B
##STR00013##
[0029] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula B. The
process is as described above.
[0030] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula C from
the compound of formula B. The process is as described above. The
present invention also provides the use of compound B in a process
for preparing
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione, or a pharmaceutically acceptable salt thereof,
especially the hydrochloride salt.
[0031] According to another aspect of the present invention, there
is provided a compound of formula C
##STR00014##
[0032] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula C. The
process is as described above.
[0033] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula D from
the compound of formula C. The process is as described above. The
present invention also provides the use of compound C in a process
for preparing
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione, or a pharmaceutically acceptable salt thereof,
especially the hydrochloride salt.
[0034] According to another aspect of the present invention, there
is provided a compound of formula D
##STR00015##
where R.sub.1, R.sub.2 and R.sub.3 are the same or different and
signify hydrogen, halogen, alkyl, nitro, amino, alkylcarbonylamino,
alkylamino or dialkylamino group; and X signifies CH.sub.2, oxygen
atom or sulphur atom; wherein the term alkyl means hydrocarbon
chains, straight or branched, containing from one to six carbon
atoms, optionally substituted by aryl, alkoxy, halogen,
alkoxycarbonyl or hydroxycarbonyl groups; the term aryl means a
phenyl or naphthyl group, optionally substituted by alkyl,
alkyloxy, halogen or nitro group; the term halogen means fluorine,
chlorine, bromine or iodine; the term heteroaryl means
heteroaromatic group.
[0035] In an embodiment, X is O.
[0036] In an embodiment, one of R.sub.1, R.sub.2 and R.sub.3 is
hydrogen, and the others are fluorine.
[0037] In an embodiment, compound D has the formula D'
##STR00016##
[0038] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula D. The
process is as described above.
[0039] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula RY from
the compound of formula D. The process is as described above. The
present invention also provides the use of compound D in a process
for preparing
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione, or a pharmaceutically acceptable salt thereof,
especially the hydrochloride salt. Preferably, the compound D' is
used to prepare the compound RY'.
[0040] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula RY or a
pharmaceutically acceptable salt thereof,
##STR00017##
wherein, R.sub.1, R.sub.2 and R.sub.3 are the same or different and
signify hydrogen, halogen, alkyl, nitro, amino, alkylcarbonylamino,
alkylamino or dialkylamino group; and X signifies CH.sub.2, oxygen
atom or sulphur atom; which process comprises deprotecting a
compound of formula K
##STR00018##
wherein R.sub.1, R.sub.2, R.sub.3 and X are as hereinbefore defined
in formula RY and Ns signifies o-nitrophenylsulphonyl; and
optionally thereafter converting the compound RY to a
pharmaceutically acceptable salt thereof.
[0041] According to a preferred embodiment of the present
invention, the compound of formula K is prepared by reacting a
compound of formula I,
##STR00019##
wherein Ns signifies o-nitrophenylsulphonyl; with a compound of
formula JZ,
##STR00020##
wherein R.sub.1, R.sub.2, R.sub.3 and X are as hereinbefore defined
in formula RY, X signifies CH.sub.2, an oxygen atom or a sulphur
atom, and Z is selected from L-tartrate, hydrochloride, mesylate,
tosylate, trifluotoacetate, citrate, glycolate and oxalate.
[0042] According to a further preferred embodiment of the present
invention, the compound of formula I is prepared by hydroxylating a
compound of formula G
##STR00021##
wherein Ns signifies o-nitrophenylsulphonyl.
[0043] According to a further preferred embodiment of the present
invention, the compound of formula I is prepared by hydrolysing a
compound of formula H,
##STR00022##
wherein Ns signifies o-nitrophenylsulphonyl.
[0044] According to a further preferred embodiment of the present
invention, the compound of formula H is prepared by acylating a
compound of formula G,
##STR00023##
wherein Ns signifies o-nitrophenylsulphonyl.
[0045] According to a still further preferred embodiment of the
present invention, the compound of formula G is prepared by
brominating a compound of formula F,
##STR00024##
wherein Ns signifies o-nitrophenylsulphonyl.
[0046] According to a still further preferred embodiment of the
present invention, the compound of formula F is prepared by
reacting a compound of formula E,
##STR00025##
with o-nitrophenylsuplonyl chloride.
[0047] A particularly preferred process for preparing a compound of
formula RY according to the present invention is as shown in Scheme
2.
##STR00026##
The process comprises: converting benzylamine E to a compound of
formula F in the presence of o-nitrophenylsulphonyl chloride and a
suitable solvent such as methyl vinyl ketone (MVK); converting the
compound F to a compound of formula G in the presence of a
brominating agent; hydroxylating a compound G to a compound of
formula I or acetylating compound G to form a compound of formula H
followed by hydrolysing the compound H to form a compound of
formula I; reacting the compound I with a compound of formula JZ to
form a compound of formula K; and deprotecting compound K to form
compound RY, where Ns is o-nitrophenylsulphonyl, Z is selected from
L-tartrate, hydrochloride, mesylate, tosylate, trifluotoacetate,
citrate, glycolate and oxalate, R.sub.1, R.sub.2 and R.sub.3 are
the same or different and signify hydrogen, halogen, alkyl, nitro,
amino, alkylcarbonylamino, alkylamino or dialkylamino group; and X
signifies CH.sub.2, oxygen atom or sulphur atom.
[0048] In an embodiment, X is O.
[0049] In an embodiment, one of R.sub.1, R.sub.2 and R.sub.3 is
hydrogen, and the others are fluorine.
[0050] In an embodiment, Z is L-tartrate. In this embodiment,
compound JZ has the formula JT and compound JZ' has the formula
JT'.
##STR00027##
[0051] In an embodiment, compound RY has the formula RY'
##STR00028##
and the process is as defined in Scheme 2' below.
##STR00029##
[0052] In an embodiment, the conversion of compound E to compound F
is carried out in the presence of a base such as triethylamine,
tributylamine, diisopropylethylamine, N-methyl morpholine,
preferably triethylamine and a catalytic amount of a suitable
alkali metal alkoxide such as potassium tert-butoxide (t-BuOK),
sodium methoxide, sodium ethoxide or sodium tert-butoxide,
preferably, potassium tert-butoxide.
[0053] In an embodiment, the bromination of compound F is achieved
using Br.sub.2 in the presence of MeOH.
[0054] In an embodiment, the acetylation of compound G is achieved
using an alkaline metal acetate, such as potassium acetate (KOAc),
sodium acetate or cesium acetate, preferably potassium acetate, in
the presence of a suitable acid such as acetic acid (AcOH).
[0055] In an embodiment, the hydrolysis of compound H is achieved
using a suitable acid such as HCl in the presence of a suitable
solvent such as 2-propanol.
[0056] In an embodiment, the hydroxylation of compound G to a
compound of formula I is achieved by treatment with an alkaline
metal formate, such as sodium, potassium or cesium formate,
preferably potassium formate in presence of formic acid in
methanol. Suitably, the reaction temperature is about 50.degree. C.
or higher, preferably from about 50.degree. C. to the reflux
temperature of the solvent used. Most preferably, the reaction is
carried out under reflux. Advantageously, the compound of formula I
was obtained in one step procedure from compound G.
[0057] In an embodiment, the condensation of compounds I and JZ is
carried out in the presence of an alkaline metal thiocyanate, such
as potassium thiocyanate (KSCN), sodium thiocyanate and cesium
thiocyanate, preferably potassium thiocyanate or an
tetraalkylammonium thiocyanate, such as tetrabutylammonium
thiocyanate and an acid, such as acetic acid (AcOH) or propionic
acid, preferably AcOH. In another embodiment, compound I can be
condensed with the hydrochloride, mesylate, tosylate,
trifluotoacetate, citrate, glycolate or oxalate salt equivalents of
compound J as described above.
[0058] In an embodiment, deprotection of the nosyl compound K is
achieved with thioglycolic acid in a polar aprotic solvent such as
DMF, DMSO and NMP, preferably DMSO or DMF in the presence of a
base, suitably LiOH, NaOH, KOH, CsOH or quaternary ammonium
hydroxides, such as tetrabutylammonium hydroxide, preferably LiOH
or KOH. Suitably, the deprotection is carried out at room
temperature, i.e. about 25.degree. C. or at about 40.degree. C.
Advantageously, the isolated yield of compound RY ranges from 91%
to 96% and HPLC has shown the purity of the crude product to be
around 98% area (Kromasil 100 5C4 250.times.4.6 column, mobile
phase 0.1% TFA-ACN 25:75 at 1 ml/min, 270 nm).
[0059] In an embodiment, the compound RY isolated from the
deprotection step is then purified. In an embodiment, the
purification is performed via a two-step procedure comprising
formation of the HCl salt in MeOH with methanolic HCl and
crystallisation of the HCl salt of compound RY from toluene after
removal of MeOH, followed by isolation of the compound RY in free
base form. In an embodiment, the overall yield of the two-step
purification process is about 85%. In another embodiment, the
purification is performed via a re-slurry in 2-butanone. In an
embodiment, the yield of the purification process is about 85%. In
an embodiment, the compound RY is RY'.
[0060] According to another aspect of the present invention, there
is provided a compound RY or RY', and pharmaceutically acceptable
salts thereof, prepared as described above.
[0061] According to another aspect of the present invention, there
is provided a compound of formula F, wherein Ns is
o-nitrophenylsulphonyl.
##STR00030##
[0062] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula F. The
process is as described above.
[0063] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula G as
described above from the compound of formula F. The process is as
described above. The present invention also provides the use of
compound F in a process for preparing
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione, or a pharmaceutically acceptable salt thereof,
especially the hydrochloride salt.
[0064] According to another aspect of the present invention, there
is provided a compound of formula G, wherein Ns is
o-nitrophenylsulphonyl.
##STR00031##
[0065] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula G. The
process is as described above.
[0066] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula H as
described above from the compound of formula G. The process is as
described above. The present invention also provides the use of
compound G in a process for preparing
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione, or a pharmaceutically acceptable salt thereof,
especially the hydrochloride salt.
[0067] According to another aspect of the present invention, there
is provided a compound of formula H, wherein Ns is
o-nitrophenylsulphonyl.
##STR00032##
[0068] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula H. The
process is as described above.
[0069] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula I as
described above from the compound of formula H. The process is as
described above. The present invention also provides the use of
compound H in a process for preparing
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione, or a pharmaceutically acceptable salt thereof,
especially the hydrochloride salt.
[0070] According to another aspect of the present invention, there
is provided a compound of formula I, wherein Ns is
o-nitrophenylsulphonyl.
##STR00033##
[0071] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula I. The
process is as described above.
[0072] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula K as
described above from the compound of formula I. The process is as
described above. The present invention also provides the use of
compound I in a process for preparing
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione, or a pharmaceutically acceptable salt thereof,
especially the hydrochloride salt.
[0073] According to another aspect of the present invention, there
is provided a compound of formula K
##STR00034##
where Ns is o-nitrophenylsulphonyl, R.sub.1, R.sub.2 and R.sub.3
are the same or different and signify hydrogen, halogen, alkyl,
nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group;
and X signifies CH.sub.2, oxygen atom or sulphur atom; wherein the
term alkyl means hydrocarbon chains, straight or branched,
containing from one to six carbon atoms, optionally substituted by
aryl, alkoxy, halogen, alkoxycarbonyl or hydroxycarbonyl groups;
the term aryl means a phenyl or naphthyl group, optionally
substituted by alkyl, alkyloxy, halogen or nitro group; the term
halogen means fluorine, chlorine, bromine or iodine; the term
heteroaryl means heteroaromatic group.
[0074] In an embodiment, X is O.
[0075] In an embodiment, one of R.sub.1, R.sub.2 and R.sub.3 is
hydrogen, and the others are fluorine.
[0076] In an embodiment, compound K has the formula K'
##STR00035##
[0077] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula K. The
process is as described above.
[0078] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula RY as
described above from the compound of formula K. The process is as
described above. The present invention also provides the use of
compound K in a process for preparing
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione, or a pharmaceutically acceptable salt thereof,
especially the hydrochloride salt.
[0079] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula K'. The
process is as described above.
[0080] According to another aspect of the present invention, there
is provided a process for preparing a compound of formula RY' as
described above from the compound of formula K'. The process is as
described above. The present invention also provides the use of
compound K' in a process for preparing
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione, or a pharmaceutically acceptable salt thereof,
especially the hydrochloride salt.
[0081] According to another aspect of the present invention, there
is provided a pharmaceutical composition comprising a compound RY
or RY', or a pharmaceutically acceptable salt thereof, prepared as
described above together with one or more
pharmaceutically-acceptable excipients.
[0082] According to another aspect of the present invention, there
is provided a composition comprising RY or RY', or a
pharmaceutically acceptable salt thereof, preferably a
therapeutically effective amount of compound RY or RY', or a
pharmaceutically acceptable salt thereof, prepared as described
above in combination with a pharmaceutically effective carrier and
one or more of the compounds selected from the classes described
below.
[0083] In particular, the compound RY or RY' as prepared by the
present invention may be combined with one or more of the following
classes of compounds: diuretics; beta-adrenergic antagonists;
alpha2-adrenergic agonists; alpha1-adrenergic antagonists; dual
beta- and alpha-adrenergic antagonists; calcium channel blockers;
potassium channel activators; anti-arrhythmics; ACE inhibitors; AT1
receptor antagonists; renin inhibitors; lipid lowerers,
vasopeptidase inhibitors; nitrates; endothelin antagonists; neutral
endopeptidase inhibitors; anti-angiotensin vaccines; vasodilators;
phosphodiesterase inhibitors; cardiac glycosides; serotonin
antagonists; and CNS acting agents.
[0084] The most useful diuretics include: [0085] (1) Loop
diuretics, in particular, furosemide, bumetanide, ethacrynic acid,
torasemide, azosemide, muzolimine, piretanide, tripamide. [0086]
(2) Thiazide diuretics, in particular, bendroflumethiazole,
chlorothiazide, hydrochlorothiazide, hydroflumethiazide,
methylclothiazide, polythiazide, trichlormethiazide. [0087] (3)
Thiazide-like diuretics, in particular, chlorthalidone, indapamide,
metozalone, quinethazone. [0088] (4) Potassium sparing diuretics,
in particular, amiloride, triamterene. [0089] (5) Aldosterone
antagonists, in particular, spirolactone, canrenone, eplerenone.
[0090] (6) Combinations of the above described diuretics.
[0091] More than one of the aforementioned diuretics may be
used.
[0092] The most useful beta-adrenergic antagonists include:
timolol, metoprolol, atenolol, propranolol, bisoprolol, nebivolol.
More than one of the aforementioned beta-adrenergic antagonists may
be used.
[0093] The most useful alpha2-adrenergic agonists include:
clonidine, guanabenz, guanfacine. More than one of the
aforementioned alpha2-adrenergic agonists may be used.
[0094] The most useful alpha1-adrenergic antagonists include:
prazosin, doxazosin, phentolamine. More than one of the
aforementioned alpha1-adrenergic antagonists may be used.
[0095] The most useful dual beta- and alpha-adrenergic antagonists
(other than those mentioned elsewhere in the specification)
include: carvedilol, labetalol. More than one of the aforementioned
dual beta- and alpha-adrenergic antagonists may be used.
[0096] Potassium channel activators include nicorandil.
[0097] The most useful calcium channel blockers include:
amlodipine, bepridil, diltiazem, felodipine, isradipine,
nicardipine, nifedipine, nimodipine, nisoldipine, verapamil. More
than one of the aforementioned calcium channel blockers may be
used.
[0098] Anti-arrhythmics other than those mentioned elsewhere in the
specification include: sodium channel blockers such as quinidine,
procainamide, disopyramide, lidocaine, mexiletine, tocainide,
phenyloin, encainide, flecainide, moricizine, and propafenone;
potassium channel blockers such as: amiodarone, bretylium,
ibutilide, dofetilide, azimilide, clofilium, tedisamil, sematilide,
sotalol; and esmolol, propranolol, metoprolol. More than one of the
anti-arrhythmics mentioned in the specification may be used.
[0099] The most useful ACE inhibitors include: benzepril,
captopril, enalapril, fosinopril, lisinopril, imidapril, moexipril,
perindopril, quinapril, ramipril, trandolapril. More than one of
the aforementioned ACE inhibitors may be used.
[0100] The most useful AT1 receptor antagonists include:
candesartan, irbesartan, losartan, telmisartan, valsartan,
eprosartan. More than one of the aforementioned AT1 receptor
antagonists may be used.
[0101] Lipid lowerers include: statins such as atorvastatin,
cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin,
pravastatin, rosuvastatin, simvastatin; bile acid sequestrants such
as cholestyramine, colestipol and colesevelam; cholesterol
absorption inhibitors such as ezetimibe; fibrates such as
fenofibrate, gemfibrozil; niacin. More than one of the
aforementioned lipid lowerers may be used.
[0102] The most useful nitrates include organic nitrates such as:
amyl nitrite, nitroglycerin, isosorbide dinitrate,
isosorbide-5-mononitrate, erythrityl tetranitrate. More than one of
the aforementioned organic nitrates may be used.
[0103] Endothelin antagonists include: bosentan, sitaxsentan. More
than one of the aforementioned endothelin antagonists may be
used.
[0104] The most useful vasodilators (other than those mentioned
elsewhere in the specification) include: hydralazine, minoxidil,
sodium nitroprusside, diazoxide. More than one of the
aforementioned vasodilators may be used.
[0105] The most useful phosphodiesterase inhibitors include:
milrinone, inaminone. More than one of the aforementioned
phosphodiesterase inhibitors may be used.
[0106] Cardiac glycosides include: allocar, corramedan, digitoxin,
digoxin, lanoxin, purgoxin, cedilanid-D, crystodigin, lanoxicaps.
More than one of the aforementioned cardiac glycosides may be
used.
[0107] Serotonin antagonists include: clozapine, loxapine,
olanzapine, risperidone, ziprasidone, ritanserin, ketanserin,
amoxapine. More than one of the aforementioned serotonin
antagonists may be used.
[0108] CNS acting agents other than those already mentioned
elsewhere in this specification include imidazoline agonists such
as moxonidine. The most useful CNS acting agent is methyldopa.
[0109] The most useful renin inhibitors include: aliskiren,
enalkiren, ditekiren, terlakiren, remikiren, zankiren, ciprokiren.
More than one of the aforementioned renin inhibitors may be
used.
[0110] The most useful vasopeptidase inhibitors include:
omapatrilat, sampatrilat, gemopatrilat. More than one of the
aforementioned vasopeptidase inhibitors may be used.
[0111] Other pharmaceuticals used in treating heart failure may
also be combined with the compound RY or RY' as prepared by the
present invention. These include calcium sensitisers; HMG CoA
reductase inhibitors; vasopressin antagonists; adenosine A1
receptor antagonists; atrial natriuretic peptide (ANP) agonists;
chelating agents; corticotrophin-releasing factor receptor;
glucagon-like peptide-1 agonists; sodium, potassium ATPase
inhibitors; advanced glycosylation end-products (AGE) crosslink
breakers; mixed neprilysin/endothelin-converting enzyme (NEP/ECE)
inhibitors; nociceptin receptor (ORL-1) agonists (e.g. alprazolam);
xanthine oxidase inhibitors; benzodiazepine agonists; cardiac
myosin activators; chymase inhibitors; endothelial nitric oxide
synthase (ENOS) transcription enhancers; neutral endopeptidase
inhibitors such as thiorphan.
[0112] The invention also envisages the use of nepicastat with the
classes of compounds described above.
[0113] For the preparation of pharmaceutical compositions of
compound RY or RY', inert pharmaceutically acceptable carriers are
admixed with the active compound. The pharmaceutically acceptable
carriers may be either solid or liquid. Solid form preparations
include powders, tablets, dispersible granules and capsules. A
carrier can be one or more substances which may also act as
diluents, flavouring agents, solubilizers, lubricants, suspending
agents, binders or tablet disintegrating agents; it may also be an
encapsulating material.
[0114] Preferably, the pharmaceutical preparation is in unit dosage
form, e.g. packaged preparation, the package containing discrete
quantities of preparation such as packeted tablets, capsules and
powders in vials or ampoules.
[0115] The dosages may be varied depending on the requirement of
the patient, the severity of the disease and the particular
compound being employed. For convenience, the total daily dosage
may be divided and administered in portions throughout the day.
Suitable administration regimes for the compounds RY or RY' are
thrice daily, twice daily, once daily, once every other day to once
weekly. It is expected that once or twice per day administration
will be most suitable. Determination of the proper dosage for a
particular situation is within the skill of those in the medical
art.
[0116] According to another aspect of the invention, there is
provided a compound RY or RY' prepared as described above, for use
as a medicament.
[0117] According to another aspect of the invention, there is
provided the use of a compound RY or RY' prepared as described
above, in the manufacture of a medicament for treating disorders
where a reduction in the hydroxylation of dopamine to noradrenaline
is of therapeutic benefit.
[0118] The compound RY or RY' may also be used in conjunction with
one or more compounds selected from the following classes of
compounds: diuretics; beta-adrenergic antagonists;
alpha2-adrenergic agonists; alpha1-adrenergic antagonists; dual
beta- and alpha-adrenergic antagonists; calcium channel blockers;
potassium channel activators; anti-arrhythmics; ACE inhibitors; AT1
receptor antagonists; renin inhibitors; lipid lowerers,
vasopeptidase inhibitors; nitrates; endothelin antagonists; neutral
endopeptidase inhibitors; anti-angiotensin vaccines; vasodilators;
phosphodiesterase inhibitors; cardiac glycosides; serotonin
antagonists; CNS acting agents; calcium sensitisers; HMG CoA
reductase inhibitors; vasopressin antagonists; adenosine A1
receptor antagonists; atrial natriuretic peptide (ANP) agonists;
chelating agents; corticotrophin-releasing factor receptor;
glucagon-like peptide-1 agonists; sodium, potassium ATPase
inhibitors; advanced glycosylation end-products (AGE) crosslink
breakers; mixed neprilysin/endothelin-converting enzyme (NEP/ECE)
inhibitors; nociceptin receptor (ORL-1) agonists (e.g. alprazolam);
xanthine oxidase inhibitors; benzodiazepine agonists; cardiac
myosin activators; chymase inhibitors; endothelial nitric oxide
synthase (ENOS) transcription enhancers; and neutral endopeptidase
inhibitors such as thiorphan.
[0119] As used herein, the term treatment and variations such as
`treat` or `treating` refer to any regime that can benefit a human
or non-human animal. The treatment may be in respect of an existing
condition or may be prophylactic (preventative treatment).
Treatment may include curative, alleviation or prophylactic
effects. Treatment with a compound RY or RY' in combination with
one of the other classes of compounds includes simultaneous and
sequential administration of the two or more drugs.
[0120] According to another aspect of the invention, there is
provided the use of a compound RY or RY' prepared as described
above, in the manufacture of a medicament for treating a subject
afflicted by an anxiety disorder.
[0121] Anxiety disorders include but are not restricted to
generalized anxiety disorders, social anxiety disorders,
post-traumatic stress disorder, acute distress disorder, obsessive
compulsive disorders, panic disorders such as panic attacks, and
phobias such as agoraphobia, social phobias, specific phobias.
Further, anxiety disorders treatable using compounds of the present
invention may be found in on pages 429-484 of American Psychiatric
Association: Diagnostic and Statistic Manual of Mental Disorders,
4th edition, Text Revision, Washington, D.C., American Psychiatric
Association, 2000.
[0122] According to another aspect of the invention, there is
provided the use of a compound RY or RY' prepared as described
above, in the manufacture of a medicament for treating
migraine.
[0123] According to another aspect of the invention, there is
provided the use of a compound RY or RY' prepared as described
above, in the manufacture of a medicament for treating a subject
afflicted by a cardiovascular disorder.
[0124] According to another aspect of the invention, there is
provided the use of a compound RY or RY' prepared as described
above, in the manufacture of a medicament for treating
hypertension, or chronic or congestive heart failure.
[0125] According to another aspect of the invention, there is
provided the use of a compound RY or RY' prepared as described
above, in the manufacture of a medicament for treating one or more
of the following indications: angina, arrhythmias, and circulatory
disorders such as Raynaud's phenomenon.
[0126] According to another aspect of the invention, there is
provided the use of a compound RY or RY' prepared as described
above, in the manufacture of a medicament for use in inhibiting
dopamine-.beta.-hydroxylase.
[0127] According to another aspect of the invention, there is
provided a method of treating anxiety disorders comprising
administering a therapeutically effective amount of a compound RY
or RY' prepared as described above to a patient in need
thereof.
[0128] According to another aspect of the invention, there is
provided a method of treating migraine comprising administering a
therapeutically effective amount of a compound RY or RY' prepared
as described above to a patient in need thereof.
[0129] According to another aspect of the invention, there is
provided a method of treating cardiovascular disorders comprising
administering a therapeutically effective amount of a compound RY
or RY' prepared as described above to a patient in need
thereof.
[0130] According to another aspect of the invention, there is
provided a method of treating hypertension comprising administering
a therapeutically effective amount of a compound RY or RY' prepared
as described above to a patient in need thereof.
[0131] According to another aspect of the invention, there is
provided a method of treating chronic or congestive heart failure
comprising administering a therapeutically effective amount of a
compound of RY or RY' prepared as described above to a patient in
need thereof.
[0132] According to another aspect of the invention, there is
provided a method of treating one or more of the following
indications: angina, arrhythmias, and circulatory disorders such as
Raynaud's phenomenon, comprising administering a therapeutically
effective amount of a compound RY or RY' prepared as described
above to a patient in need thereof.
[0133] The above-described methods of treatment may further
comprise simultaneous or sequential administration of a drug from
one of the following classes of compounds: diuretics;
beta-adrenergic antagonists; alpha2-adrenergic agonists;
alpha1-adrenergic antagonists; dual beta- and alpha-adrenergic
antagonists; calcium channel blockers; potassium channel
activators; anti-arrhythmics; ACE inhibitors; AT1 receptor
antagonists; renin inhibitors; lipid lowerers, vasopeptidase
inhibitors; nitrates; endothelin antagonists; neutral endopeptidase
inhibitors; anti-angiotensin vaccines; vasodilators;
phosphodiesterase inhibitors; cardiac glycosides; serotonin
antagonists; CNS acting agents; calcium sensitisers; HMG CoA
reductase inhibitors; vasopressin antagonists; adenosine A1
receptor antagonists; atrial natriuretic peptide (ANP) agonists;
chelating agents; corticotrophin-releasing factor receptor;
glucagon-like peptide-1 agonists; sodium, potassium ATPase
inhibitors; advanced glycosylation end-products (AGE) crosslink
breakers; mixed neprilysin/endothelin-converting enzyme (NEP/ECE)
inhibitors; nociceptin receptor (ORL-1) agonists (e.g. alprazolam);
xanthine oxidase inhibitors; benzodiazepine agonists; cardiac
myosin activators; chymase inhibitors; endothelial nitric oxide
synthase (ENOS) transcription enhancers; and neutral endopeptidase
inhibitors such as thiorphan.
EXAMPLES
[0134] The following non-limiting examples describe embodiments of
the present invention.
[0135] NMR spectra were recorded at 20.degree. C., on a Bruker
Avance DPX 400 MHz, or a 600 MHz Avance III spectrometer with
solvent used as internal standard. Data are reported in the
following order: approximate chemical shift (ppm), number of
protons, multiplicity (br, broad; d d, doublet of doublet; d t,
doublet of triplet; m, multiplet; m d, multiplet of doublet; m t,
multiplet of triplet; s, singlet) and coupling constant (Hz).
Example 1
N-benzyl-4-hydroxy-3-oxobutanamide (Compound C)
[0136] To a solution of N-benzyl-3-oxobutanamide (compound A 50 g,
261 mmol) in dichloromethane (350 ml) was added bromine (14.82 ml,
288 mmol) at 0-5.degree. C., then stirred at 20-25.degree. C. for 3
hours (bromine colour disappeared). Water (300 ml) was added to the
mixture with stirring, stirred for 10 min. Organic phase was
separated, washed with sodium bicarbonate solution, dried,
evaporated to dryness (compound B). The solid residue (compound B)
dissolved in methanol (900 ml), added potassium formate (44.0 g,
523 mmol) and the mixture was heated under reflux for 2 hours.
Methanol was removed on a rotavap, the residue was taken up into
ethyl acetate (EA) (500 ml) under reflux, filtered hot, the filter
cake washed with warm EA (100 ml). The combined filtrate was cooled
to 5-10.degree. C., aged for 1.5 hours. The precipitate was
collected, washed with cold EA (50 ml), dried to give 25 g (46.1%)
of crude product, light beige. Re-crystallised from water (300 ml),
with active carbon (1 g). Filtered hot on celite, cooled in ice,
aged for 1 hour, crystals collected, washed with cold water (20
ml), dried on air overnight to give
N-benzyl-4-hydroxy-3-oxobutanamide (21 g, 101 mmol, 38.8%
yield).
[0137] .sup.1H NMR (600 MHz, 20.degree. C., DMSO) .delta.: 13.92
(0.1H, s br), 8.53 (1H, t, J=5.5 Hz), 7.32 (2H, m t, J=7.5 Hz),
7.27 (2H, m d, J=8.0 Hz), 7.24 (1H, m t, J=7.0 Hz), 5.32 (0.1H, s
br), 5.25 (1H, t, J=6.1 Hz), 4.32 (0.2H, d, J=6.1 Hz), 4.28 (1.8H,
d, J=5.9 Hz), 4.17 (1.8H, d, J=6.1 Hz), 3.89 (0.2H, s br), 3.37
(1.8H, s); .sup.13C NMR (100 MHz, 20.degree. C., DMSO) .delta.:
205.6, 166, 139.2, 128.3, 127.3, 126.9, 88.4, 67.8, 60.5, 46.6,
42.2, 41.6.
Example 2
N-benzyl-4-bromo-3-oxobutanamide (Compound B)
[0138] To a solution of N-benzyl-3-oxobutanamide (compound A 100 g,
522.9 mmol) in dichloromethane (500 ml) at 0-5.degree. C. was added
dropwise a solution of bromine (25.55 ml, 575.2 mmol) over 6 h. The
reaction mixture was warmed up to 20-25.degree. C. and stirred for
2 hours (bromine colour disappeared). An aqueous solution (600 mL)
of sodium bicarbonate (65.9 g, 784.44 mmol) was added to the
mixture. The organic layer was separated, washed with brine (200
mL), and then evaporated to dryness to give
N-benzyl-4-bromo-3-oxobutanamide (114.25 g, quantitative) and was
used in the next step without further purification.
[0139] .sup.1H NMR, 600 MHz, 20.degree. C., CDCl.sub.3) .delta.:
13.7 (0.3H, s br), 7.38-7.33 (2H, m), 7.33-7.27 (3H, m), 6.85
(0.7H, s br), 5.61 (0.3H, s br), 5.14 (0.3H, s), 4.50, 4.48 (2H, 2
d, J=5.9, J=5.7 Hz), 4.06 (1.4H, s), 3.48 (0.6; H, s), 3.68 (1.4H,
s); .sup.13C NMR (100 MHz, 20.degree. C., CDCl.sub.3)
.delta..quadrature.: 197.4, 170.7, 168.8, 164.5, 137.5, 137.4,
128.8, 128.8, 127.8, 127.8, 127.8, 127.7, 92.3, 46.6, 43.8, 43.2,
34.5, 29.4.
Example 3
N-benzyl-4-hydroxy-3-oxobutanamide (Compound C)
[0140] N-benzyl-4-bromo-3-oxobutanamide (compound B 50 g, 185.1
mmol) was dissolved in methanol (400 ml), and potassium formate
(31.14 g, 370.2 mmol) was added. The resulting mixture was heated
under reflux for 2 hours. Methanol was removed by distillation
under reduced pressure; the residue was taken up into ethyl acetate
(250 ml) under reflux, filtered hot, the filter cake washed with
warm ethyl acetate (100 ml). The combined filtrate was cooled to
-10.degree. C., aged for 1.5 hours. The precipitate was collected,
washed twice with cold ethyl acetate (2.times.25 ml), dried to give
N-benzyl-4-hydroxy-3-oxobutanamide (18.2 g, 101 mmol, 38.8%
yield).
[0141] .sup.1H NMR (600 MHz, 20.degree. C., DMSO) .delta.: 13.92
(0.1H, s br), 8.53 (1H, t, J=5.5 Hz), 7.32 (2H, m t, J=7.5 Hz),
7.27 (2H, m d, J=8.0 Hz), 7.24 (1H, m t, J=7.0 Hz), 5.32 (0.1H, s
br), 5.25 (1H, t, J=6.1 Hz), 4.32 (0.2H, d, J=6.1 Hz), 4.28 (1.8H,
d, J=5.9 Hz), 4.17 (1.8H, d, J=6.1 Hz), 3.89 (0.2H, s br), 3.37
(1.8H, s); .sup.13C NMR (100 MHz, 20.degree. C., DMSO) .delta.:
205.6, 166, 139.2, 128.3, 127.3, 126.9, 88.4, 67.8, 60.5, 46.6,
42.2, 41.6.
Example 4
(R)--N-benzyl-2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H-imid-
azol-4-yl)acetamide (Compound D')
[0142] To a mixture of
(R)-6,8-difluorochroman-3-amine(2R,3R)-2,3-dihydroxysuccinate
(compound JT', 15 g, 44.7 mmol) and potassium thiocyanate (5.22 g,
53.7 mmol) in 2-propanol (150 ml) was added acetic acid (38.4 ml,
671 mmol) followed by N-benzyl-4-hydroxy-3-oxobutanamide (compound
C, 11.13 g, 53.7 mmol) in 5 portions during 1 hours. The mixture
was heated with stirring at 80.degree. C. for 2 hours. More
N-benzyl-4-hydroxy-3-oxobutanamide (1.854 g, 8.95 mmol) and
potassium thiocyanate (0.870 g, 8.95 mmol) added, stirred for 1
hour. More N-benzyl-4-hydroxy-3-oxobutanamide (1.854 g, 8.95 mmol)
and potassium thiocyanate (0.870 g, 8.95 mmol) added, stirred for 1
hour (in total N-benzyl-4-hydroxy-3-oxobutanamide (14.83 g, 71.6
mmol) and potassium thiocyanate (6.96 g, 71.6 mmol)), purified by
HPLC at 210 nm (Kromasil 100 5C4 250.times.4.6 column, 0.1% TFA-ACN
50:50, 1 ml/min) with less than 1.5% compound JT'. Diluted with
water (110 ml) at approx 50.degree. C., cooled to 5.degree. C. and
aged for 1 hour. Precipitate was collected, washed with water. Wet
filter cake was re-slurried in water (300 ml), solution of sodium
bicarbonate (4.13 g, 49.2 mmol) in water (100 ml) was added in
portions, the mixture was stirred for 15 min, filtered, washed with
water (wet weight 21 g), dried on air to give
(R)--N-benzyl-2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H-imi-
dazol-4-yl)acetamide (12.2 g, 29.4 mmol, 65.6% yield).
[0143] .sup.1H NMR (600 MHz, 20.degree. C., DMSO) .delta.: 12.22
(1H, s br), 8.56 (1H, t, J=5.9 Hz), 7.26-7.10 (6H, m), 6.90 (1H, d
br, J=8.8 Hz), 6.81 (1H, s), 5.27 (1H, s br), 4.60 (2H, br), 4.32
(1H, m d, J=10.3 Hz), 4.25 (2H, m), 3.63 (2H, d, J=1.7 Hz), 2.90
(1H, dd, J=5.2, 16.0 Hz); .sup.13C NMR (100 MHz, 20.degree. C.,
DMSO) .delta.: 168.3, 160.4, 155.1 (d d, J=11.2, 238.5 Hz), 150.5
(d d, J=12.9, 246.5 Hz), 139.1, 138.3 (d d, J=3.2, 11.5 Hz), 128.3,
127.4, 126.9, 126, 124.8 (d d, J=2.2, 9.4 Hz), 114.3, 111.2 (d d,
J=3.5, 23.0 Hz), 102.6 (d d, J=22.1, 27.5 Hz), 64.5, 49.6, 42.5,
31.1, 26.5
Example 5
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3-
H)-thione (Compound RY')
[0144] To a solution of
(R)--N-benzyl-2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H-imi-
dazol-4-yl)acetamide (1 g, 2.407 mmol) in tetrahydrofuran (10 ml)
was added sodium borohydride (0.455 g, 12.03 mmol) followed by
solution of boron trifluoride etherate (1.525 ml, 12.03 mmol) in
tetrahydrofuran (5 ml) with ice cooling dropwise during 10 min,
allowed to warm up naturally and stirred at 20-25.degree. C. under
Ar. After 7 hours still 7.5% of starting material (SM), the
reaction was left overnight with stirring. Quenched with 1N
hydrochloric acid (5 ml, 5.00 mmol) with ice-cooling (first drops
caused intensive foaming), pH to 1 with 6N hydrochloric acid (2 ml,
12.00 mmol), the mixture refluxed for 30 min. Diluted with water,
THF removed on a rotavap (crystallisation occurred), the residue
aged for 1 hour at RT. Precipitate collected, washed with water.
Dried at 50.degree. C. in vacuum to give 1.13 g of solid. Dissolved
in Methanol (15.00 ml) and water (2.3 ml), heated to reflux, 1N
sodium hydroxide (2.65 ml, 2.65 mmol) added (pH 8-9). No immediate
crystallisation, crystallised at approx 50.degree. C. Cooled to
20-25.degree. C., aged for 30 min, precipitate collected, washed
with MeOH, dried in vacuum at 50.degree. C. to give
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione (0.73 g, 1.818 mmol, 76% yield).
[0145] .sup.1H NMR (400 MHz, DMSO, 20.degree. C.) .delta.: 12.05
(1H, br, NH), 7.31-7.21 (4H, m), 7.21-7.12 (2H, m), 6.89 (1H, d,
br, J=9.0 Hz), 6.74 (1H, s), 5.19 (1H, s, br), 4.82 (1H, s, br),
4.41 (1H, s, br), 4.28 (1H, m, J=3.5, 11.0 Hz), 3.68 (2H, s), 2.87
(1H, dd, J=6.0, 16.5 Hz), 2.77-2.57 (4H, m); .sup.13C NMR (100 MHz,
DMSO, 20.degree. C.) .delta.: 160.3, 155.1 (dd, J=11.0, 238.0 Hz),
150.5 (dd, J=13.5, 246.5 Hz), 140.8, 138.4 (dd, J=3.5, 11.5 Hz),
129.8, 128.1, 127.9, 126.5, 124.8 (dd, J=2.5, 9.5 Hz), 112.4, 111.2
(dd, J=3.5, 22.5 Hz), 102.7 (dd, J=22.0, 27.5), 64.8, 52.7, 48.9,
47.6, 27.0, 24.8.
Example 6
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3-
H)-thione (Compound RY')
[0146] To a solution of
(R)--N-benzyl-2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H-imi-
dazol-4-yl)acetamide (16.62 g, 40 mmol) in tetrahydrofuran (133 ml)
was added sodium borohydride (3.78 g, 100 mmol). The suspension was
then cooled to 0.degree. C. and a solution of boron trifluoride
tetrahydrofuran (14.56 ml, 132 mmol) in tetrahydrofuran (85 ml).
The mixture was warmed up to room temperature (20-25.degree. C.)
and stirred for 24 hours. After cooling to 0.degree. C., 1N
hydrochloric acid (64 ml, 64 mmol), pH to 1 with 6N hydrochloric
acid (17.7 ml, 108 mmol), and the mixture was refluxed for 30 min.
Tetrahydrofuran was removed under reduced pressure. The precipitate
was collected, washed with water (50 mL). The wet solid was
suspended in a mixture of methanol (250 ml) and water (38 ml). The
suspension was heated to reflux until complete dissolution; 1N
sodium hydroxide (45 ml, 48 mmol) was added (pH 8-9). The
crystallization occurred at approx 50.degree. C. The suspension was
cooled to 15.degree. C., aged for 3 hours. The precipitate was
collected, washed with methanol (33 mL), dried in vacuum at
50.degree. C. to give
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione (12.5 g, 30.01 mmol, 76% yield).
[0147] .sup.1H NMR (400 MHz, DMSO, 20.degree. C.) .delta.: 12.05
(1H, br, NH), 7.31-7.21 (4H, m), 7.21-7.12 (2H, m), 6.89 (1H, d,
br, J=9.0 Hz), 6.74 (1H, s), 5.19 (1H, s, br), 4.82 (1H, s, br),
4.41 (1H, s, br), 4.28 (1H, m, J=3.5, 11.0 Hz), 3.68 (2H, s), 2.87
(1H, dd, J=6.0, 16.5 Hz), 2.77-2.57 (4H, m); .sup.13C NMR (100 MHz,
DMSO, 20.degree. C.) .delta.: 160.3, 155.1 (dd, J=11.0, 238.0 Hz),
150.5 (dd, J=13.5, 246.5 Hz), 140.8, 138.4 (dd, J=3.5, 11.5 Hz),
129.8, 128.1, 127.9, 126.5, 124.8 (dd, J=2.5, 9.5 Hz), 112.4, 111.2
(dd, J=3.5, 22.5 Hz), 102.7 (dd, J=22.0, 27.5), 64.8, 52.7, 48.9,
47.6, 27.0, 24.8.
Example 7
N-benzyl-2-nitro-N-(3-oxobutyl)benzenesulfonamide (Compound F)
[0148] To a solution of benzylamine (10.92 ml, 100 mmol) in
dichloromethane (DCM) (150 ml) was added triethylamine (13.67 ml,
100 mmol) followed by a solution of 2-nitrobenzene-1-sulfonyl
chloride (22.16 g, 100 mmol) in DCM (70 ml) at 5-10.degree. C. with
stirring. The mixture was stirred for 1 hour (complete by HPLC),
stirring continued for 1 hour, washed with water, brine, most of
DCM removed on a rotavap, Ethyl acetate (150 ml) was added, another
25-30 ml distilled off under reduced pressure. To the resulting
solution potassium tert-butoxide (0.561 g, 5.00 mmol) was added
followed by methyl vinyl ketone (9.07 ml, 110 mmol) with stirring
in one portion at 20-25.degree. C. The mixture was stirred for 1
hour at 20-25.degree. C., diluted with heptane (70 ml), washed with
brine+1N HCl (5 ml), organic phase was dried (MgSO.sub.4),
evaporated to approx 100 ml, seeded with crystals of compound F
(crystallisation started), cooled to 0-5.degree. C., diluted slowly
with heptane to approx 200 ml. The mixture was aged in ice for 1
hour, crystals collected, washed with heptane, dried on air to give
N-benzyl-2-nitro-N-(3-oxobutyl)benzenesulfonamide (31.4 g, 87 mmol,
87% yield).
[0149] .sup.1HNMR (600 MHz, 20.degree. C., CDCl.sub.3) .delta.:
7.98 (1H, m), 7.71 (1H, m), 7.68-7.64 (2H, m), 7.35-7.27 (5H, m),
4.51 (2H, s), 3.50 (2H, m), 2.55 (2H, m), 1.97 (3H, s); .sup.13C
NMR (100 MHz, 20.degree. C., CDCl.sub.3) .delta.: 206.4, 148,
135.7, 133.6, 132.9, 131.8, 130.8, 128.8, 128.3, 128.1, 124.2,
52.8, 42.6, 42.5, 30.
Example 8
N-benzyl-2-nitro-N-(3-oxobutyl)benzenesulfonamide (Compound F)
[0150] To a solution of benzylamine (1 ml, 9.16 mmol) in ethyl
acetate (10 ml) was added triethylamine (1.252 ml, 9.16 mmol)
followed 2-nitrobenzene-1-sulfonyl chloride (2.03 g, 9.16 mmol) at
5-10.degree. C. with stirring. The mixture was stirred for 1 hour
(complete by HPLC), stirring continued for 1 hour. The reaction
mixture was quenched with water. The organic layer was separated,
washed with brine, dried, and concentrated under reduced pressure.
The residue was dissolved in ethyl acetate (8 ml) and to the
resulting solution potassium tert-butoxide (0.051 g, 0.458 mmol)
was added followed by methyl vinyl ketone (0.755 ml, 9.16 mmol)
with stirring in one portion at 20-25.degree. C. The mixture was
stirred for 2 hours at 20-25.degree. C., quenched with brine. The
organic phase was separated and the aqueous layer was back
extracted with ethyl acetate (5 mL). The combined organic layers
were washed with 0.6N HCl (10 mL), concentrated to 3 volumes. The
solution was diluted with isopropanol (20 mL), concentrated under
reduced pressure until a precipitate appeared. The resulting slurry
was then stirred at 20.degree. C. for 4 hours, filtered. The
collected solid was then washed with 2-propanol (2.times.40 mL),
dried to give N-benzyl-2-nitro-N-(3-oxobutyl)benzenesulfonamide
(2.5 g, 6.87 mmol, 75% yield).
[0151] .sup.1H NMR (600 MHz, 20.degree. C., CDCl.sub.3) .delta.:
7.98 (1H, m), 7.71 (1H, m), 7.68-7.64 (2H, m), 7.35-7.27 (5H, m),
4.51 (2H, s), 3.50 (2H, m), 2.55 (2H, m), 1.97 (3H, s); .sup.13C
NMR (100 MHz, 20.degree. C., CDCl.sub.3) .delta.: 206.4, 148,
135.7, 133.6, 132.9, 131.8, 130.8, 128.8, 128.3, 128.1, 124.2,
52.8, 42.6, 42.5, 30.
Example 9
N-benzyl-N-(4-bromo-3-oxobutyl)-2-nitrobenzenesulfonamide (Compound
G)
[0152] To a solution of
N-benzyl-2-nitro-N-(3-oxobutyl)benzenesulfonamide (compound F, 30
g, 83 mmol) in methanol (300 ml) was added bromine (4.69 ml, 91
mmol) in one portion at 20-25.degree. C. Stirred for 20 hours (no
bromine colour), water (20 ml) added, heated to reflux for 30 min,
diluted with MeOH (100 ml). The solution was cooled to 30.degree.
C. with stirring, seeded with compound G, stirred at 25-30.degree.
C. for 5 min (crystallisation occurred), cooled to 15.degree. C.,
aged for 1 hour. Crystals collected, washed with 2.times.15 ml of
MeOH (20-25.degree. C.), dried on air to give
N-benzyl-N-(4-bromo-3-oxobutyl)-2-nitrobenzenesulfonamide (19.4 g,
44.0 mmol, 53.1% yield).
[0153] .sup.1H NMR (400 MHz, 20.degree. C., CDCl.sub.3) .delta.:
8.0 (1H, m), 7.73 (1H, m), 7.70-7.66 (2H, m), 7.38-7.27 (5H, m),
4.52 (2H, s), 3.69 (2H, s), 3.55 (2H, m t, J=7.2 Hz), 2.75 (2H, m
t, J=7.1 Hz); .sup.13C NMR (100 MHz, 20.degree. C., CDCl.sub.3)
.delta.: 199.8, 148, 135.5, 133.8, 132.8, 131.8, 131, 128.9, 128.4,
128.3, 124.3, 53, 42.8, 39.1, 34.1.
Example 10
N-benzyl-N-(4-hydroxy-3-oxobutyl)-2-nitrobenzenesulfonamide
(Compound I)
[0154] A mixture of
N-benzyl-N-(4-bromo-3-oxobutyl)-2-nitrobenzenesulfonamide (16 g,
36.3 mmol) and potassium acetate (8.90 g, 91 mmol) in acetic acid
(130 ml) was heated to 110-115.degree. C. (slow reflux visible) and
stirred for 1 hour (complete by HPLC). Cooled, acetic acid (80 ml)
removed under reduced pressure, the residue distributed between DCM
(120 ml) and water (120 ml). The organic phase was washed with
water, evaporated to half of the volume, diluted with 2-propanol
(65.0 ml), the rest of DCM removed. Water (18.20 ml) was added
followed by concentrated hydrochloric acid (2.102 ml, 25.4 mmol),
residual DCM was distilled off at atmospheric pressure until head
temperature reached 77.degree. C., then stirred under reflux for 3
hours. Diluted with water (65 ml), 2-propanol removed at 60.degree.
C./180 mbar, to the biphasic residue EA (80 ml) was added followed
by sodium bicarbonate with stirring until evolution of gas stopped.
The organic phase was dried (MgSO.sub.4), evaporated to dryness to
give N-benzyl-N-(4-hydroxy-3-oxobutyl)-2-nitrobenzenesulfonamide
(13.2 g, 34.9 mmol, 96% yield).
[0155] .sup.1H NMR (400 MHz, 20.degree. C., CDCl.sub.3) .delta.:
8.0 (1H, m), 7.78-7.64 (3H, m), 7.39-7.27 (5H, m), 4.51 (2H, s),
4.03 (2H, d br, J=4.0 Hz), 3.59 (2H, m t, J=7.2 Hz), 2.83 (1H, t
br, J=4.0 Hz), 2.51 (2H, m t, J=7.0 Hz); .sup.13C NMR (100 MHz,
20.degree. C., CDCl.sub.3) .delta.: 207.3, 148, 135.4, 133.8,
132.7, 131.8, 131, 128.9, 128.3, 128.3, 124.3, 68.1, 53, 42.4,
37.7.
Example 11
N-benzyl-N-(4-hydroxy-3-oxobutyl)-2-nitrobenzenesulfonamide
(Compound I)
[0156] A suspension of
N-benzyl-N-(4-bromo-3-oxobutyl)-2-nitrobenzenesulfonamide (Compound
G, 200 mg, 0.453 mmol), formic acid (0.100 ml, 2.65 mmol) and
potassium formate (76 mg, 0.906 mmol) in methanol (2 ml) was heated
to reflux for 2 hours. The reaction mixture was then cooled to room
temperature and then filtered to remove inorganic salt. The
filtrate was then concentrated under reduced pressure, then diluted
in ethyl acetate. The resulting slurry was then filtered and the
solid was washed with ethyl acetate. The resulting combined
filtrates were concentrated under reduced pressure.
N-benzyl-N-(4-hydroxy-3-oxobutyl)-2-nitrobenzenesulfonamide
(Compound I, 169 mg, 0.447 mmol, 99% yield) was obtained as a pale
yellow oil.
[0157] .sup.1H NMR (400 MHz, 20.degree. C., CDCl.sub.3) .delta.:
8.0 (1H, m), 7.78-7.64 (3H, m), 7.39-7.27 (5H, m), 4.51 (2H, s),
4.03 (2H, d br, J=4.0 Hz), 3.59 (2H, m t, J=7.2 Hz), 2.83 (1H, t
br, J=4.0 Hz), 2.51 (2H, m t, J=7.0 Hz); .sup.13C NMR (100 MHz,
20.degree. C., CDCl.sub.3) .delta.: 207.3, 148, 135.4, 133.8,
132.7, 131.8, 131, 128.9, 128.3, 128.3, 124.3, 68.1, 53, 42.4,
37.7.
Example 12
(R)--N-benzyl-N-(2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H-i-
midazol-4-yl)ethyl)-2-nitrobenzenesulfonamide (Compound K')
[0158] To a mixture of
(R)-6,8-difluorochroman-3-amine(2R,3R)-2,3-dihydroxysuccinate
(compound JT', 1.7 g, 5.07 mmol),
N-benzyl-N-(4-hydroxy-3-oxobutyl)-2-nitrobenzenesulfonamide
(compound I, 2.303 g, 6.08 mmol) in acetic acid (12.5 ml) was added
potassium thiocyanate (0.591 g, 6.08 mmol) in one portion. The
mixture was heated with stirring at 100.degree. C. for 3 hours
under HPLC control, cooled to 20.degree. C., diluted with
2-propanol (55 ml), cooled to 0.degree. C., aged for 1 hour. The
precipitate collected, washed with cold 2-propanol (55 ml), dried
to give 12.54 g. The solid was suspended in a mixture of water (38
ml) and ethanol (EtOH) (19 ml), solid sodium bicarbonate (2.255 g,
26.8 mmol) was added in portions with stirring at 20-25.degree. C.,
stirred for 30 min. Solid collected, washed with water, dried to
give
(R)--N-benzyl-N-(2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H--
imidazol-4-yl)ethyl)-2-nitrobenzenesulfonamide (compound K', 8.4 g,
14.32 mmol, 64.0% yield).
[0159] .sup.1H NMR (600 MHz, 20.degree. C., DMSO) .delta.: 12.16
(1H, s br), 8.04 (1H, dd, J=1.2, 8.0 Hz), 8.0 (1H, dd, J=1.3, 8.0
Hz), 7.89 (1H, d t, J=1.3, 7.6 Hz), 7.81 (1H, d t, J=1.3, 7.8 Hz),
7.28-7.14 (6H, m), 6.88 (1H, d br, J=8.5 Hz), 6.68 (1H, s), 5.03
(1H, br), 4.56 (2H, s), 4.56 (1H, br), 4.18 (1H, m d, J=10.5 Hz),
4.18 (1H, br), 3.41 (2H, m), 2.76 (1H, dd, J=5.5, 16.5 Hz), 2.61
(2H, m); .sup.13C NMR (150 MHz, 20.degree. C., DMSO) .delta.:
160.8, 155.1 (d d, J=11.2, 238.0 Hz), 150.5 (d d, J=13.3, 246.7
Hz), 147.5, 138.4 (d d, J=3.0, 11.5 Hz), 135.9, 134.7, 132.6,
131.7, 129.9, 128.6, 128.1, 127.9, 127, 124.5 (d d, J=2.5, 10.0
Hz), 124.4, 113, 111.1 (d d, J=3.5, 22.8 Hz), 102.7 (d d, J=22.0,
27.0 Hz), 64.5, 50.8, 48.8, 46.3, 26.9, 23.4.
Example 13
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3-
H)-thione (Compound RY' Crude)
[0160] To a solution of
(R)--N-benzyl-N-(2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H--
imidazol-4-yl)ethyl)-2-nitrobenzenesulfonamide (compound K', 8 g,
13.64 mmol) and 2-mercaptoacetic acid (2.84 ml, 40.9 mmol) in
dimethylformamide (DMF) (80 ml) was added 10N potassium hydroxide
(10.23 ml, 102 mmol) in one portion with water cooling and the
mixture was stirred at 20-25.degree. C. under HPLC control for 3
hours. Methanol-water 1:1 (160 ml) was slowly added with stirring,
the mixture was stirred for 2 hours at 20-25.degree. C. Precipitate
was collected, washed with MeOH-water 1:1 (80 ml), dried to give
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione (4.96 g, 12.35 mmol, 91% yield).
[0161] .sup.1H NMR (400 MHz, DMSO, 20.degree. C.) .delta.: 12.05
(1H, br, NH), 7.31-7.21 (4H, m), 7.21-7.12 (2H, m), 6.89 (1H, d,
br, J=9.0 Hz), 6.74 (1H, s), 5.19 (1H, s, br), 4.82 (1H, s, br),
4.41 (1H, s, br), 4.28 (1H, m, J=3.5, 11.0 Hz), 3.68 (2H, s), 2.87
(1H, dd, J=6.0, 16.5 Hz), 2.77-2.57 (4H, m); .sup.13C NMR (100 MHz,
DMSO, 20.degree. C.) .delta.: 160.3, 155.1 (dd, J=11.0, 238.0 Hz),
150.5 (dd, J=13.5, 246.5 Hz), 140.8, 138.4 (dd, J=3.5, 11.5 Hz),
129.8, 128.1, 127.9, 126.5, 124.8 (dd, J=2.5, 9.5 Hz), 112.4, 111.2
(dd, J=3.5, 22.5 Hz), 102.7 (dd, J=22.0, 27.5), 64.8, 52.7, 48.9,
47.6, 27.0, 24.8.
Example 14
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3-
H)-thione (Compound RY' Crude)
[0162] To a solution of potassium hydroxide (5M aqueous solution,
52.5 ml, 263 mmol) in water at 10.degree. C. was added dropwise
2-mercaptoacetic acid (8.30 ml, 119 mmol). The resulting solution
was stirred at room temperature for 10 minutes and a solution of
(R)--N-benzyl-N-(2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H--
imidazol-4-yl)ethyl)-2-nitrobenzenesulfonamide (28 g, 47.7 mmol) in
DMSO (150 ml) was added dropwise over 20 minutes. During the
addition of KOH, an exothermic event was observed. The resulting
slurry was stirred at 40.degree. C. under HPLC control for 3 h. The
reaction was then cooled to 20.degree. C. and methanol (105 ml) was
added followed by water (45 ml). The resulting slurry was aged for
30 minutes at 20.degree. C. and then filtered. The beige solid was
successively washed with water/MeOH (9:1) (100 ml), water (200 ml)
and finally methyl tert-butyl ether (MTBE) (50 ml), dried to give
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione (compound RY', 18.3 g, 12.35 mmol, 96% yield).
Example 15
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3-
H)-thione hydrochloride (HCl Salt of Compound RY' Purified)
[0163] To a suspension of
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione (2 g, 4.98 mmol) in methanol (MeOH) (30 ml) was added
1.5M hydrochloric acid (3.32 ml, 4.98 mmol) in MeOH to give a clear
solution. To the solution Toluene (30.0 ml) was added, MeOH (30 ml)
was removed on a rotavap followed by addition of toluene (20 ml).
The mixture was aged with stirring for 1 hours at 0-5.degree. C.,
the precipitate collected, washed with toluene (10 ml), dried in
vacuum at 50.degree. C. to give 2.05 g (94%) of purified
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione hydrochloride.
[0164] .sup.1H NMR (400 MHz, DMSO, 20.degree. C.) .delta.: 12.32
(1H, br), 9.52 (2H, s, br), 7.57 (2H, m, J=7.8 Hz), 7.41 (3H, m),
7.16 (1H, m), 6.94 (1H, d, br, J=9 Hz), 6.91 (1H, d, J=2.5 Hz),
5.18 (1H, s, br), 4.84 (1H, s, br), 4.42 (1H, s, br), 4.36 (1H, m,
J=10.5), 4.16 (2H, br), 3.08 (4H, m), 2.93 (1H, dd, J=5.5 and 16.5
Hz); .sup.13C NMR (100 MHz, DMSO, 20.degree. C.) .delta.: 160.0,
155.1 (dd, J=11.5 and 239.0 Hz), 150.5 (dd, J=13.5 and 246.5 Hz),
138.4 (dd, J=3.0 and 11.5 Hz), 132.1, 130.0, 128.9, 128.7, 126.3,
124.6 (dd, J=2.0 and 9.0 Hz), 113.7, 111.2 (dd, J=3.5 and 22.5 Hz),
102.7 (dd, J=22.0 and 27.0 Hz), 64.6, 49.8, 48.9, 44.8, 27.0,
21.0.
Example 16
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3-
H)-thione (Compound RY' Purified)
[0165]
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidaz-
ole-2(3H)-thione hydrochloride (8 g, 18.27 mmol) was dissolved in
methanol (120 ml) at 40-45.degree. C., diluted with water (18.00
ml), crystallisation occurred. The precipitate was dissolved with
heating to 67-68.degree. C. and stirring. To the solution 1N sodium
hydroxide (19.18 ml, 19.18 mmol) was added dropwise during 1 hour
via a syringe pump. The mixture was aged for 30 min at 67.degree.
C., cooled to 20.degree. C. during 1 hour, aged at 20.degree. C.
for 30 min. Crystals were collected, washed with MeOH-water 1:1 (36
ml), dried to give
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione (6.7 g, 16.69 mmol, 91% yield).
Example 17
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3-
H)-thione (Compound RY' Purified)
[0166] A suspension of
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione (15 g, 37.4 mmol) in 2-butanone (MEK, 150 ml) was heated
to 80.degree. C. The resulting slurry was stirred for 2 hours at
80.degree. C. and then slowly cooled to 20.degree. C. over 2 hours.
The solid was filtered, washed with 2-propanol (45 mL) and then
dried in vacuum at 50.degree. C.
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(-
3H)-thione (12.6 g, 31.38 mmol, 84%) was obtained as an off white
solid.
Example 18
N-benzyl-N-(4-hydroxy-3-oxobutyl)-2-nitrobenzenesulfonamide
(Compound I)
[0167] Reaction of 1,1-dimethoxyacetone with dimethylformamide
dimethyl acetal produced N,N-dimethyl enaminone which upon
treatment with benzylamine gave N-benzyl enaminone. The latter was
fully reduced to amino alcohol and N-protected with Ns-group.
Acidic cleavage of acetal and simultaneous rearrangement afforded
after chromatographic purification the target hydroxy ketone
(Scheme 3).
##STR00036##
[0168] The steps were carried out as follows.
(a) (E)-4-(Dimethylamino)-1,1-dimethoxybut-3-en-2-one
[0169] prepared as described in Maury et al, J. Heterocyclic Chem.,
1978, 15, p. 1041
(b) (E)-4-(Benzylamino)-1,1-dimethoxybut-3-en-2-one
[0170] A mixture of
(E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (11 g, 63.5 mmol)
and benzylamine (6.94 ml, 63.5 mmol) in toluene (130 ml) was
stirred under reflux for 4 hours. Evaporated to dryness under
vacuum, the residue was applied on a column, eluted with petroleum
ether-ethyl acetate mixture 3:1, fractions collected to give
(E)-4-(benzylamino)-1,1-dimethoxybut-3-en-2-one (6.4 g, 27.2 mmol,
42.8% yield) as dark yellow oil.
(c) 4-(Benzylamino)-1,1-dimethoxybutan-2-ol
[0171] To a solution of
(E)-4-(benzylamino)-1,1-dimethoxybut-3-en-2-one (4.71 g, 20 mmol)
in a mixture of 2-Propanol (60 ml) and Water (4.80 ml) was added
sodium borohydride (3.03 g, 80 mmol) in portions at 20-25.degree.
C., the mixture was stirred overnight. Quenched with 5N HCl to pH 7
(approx 10 ml), pH adjusted to 8-9 with 5N NaOH, diluted with MTBE
(100 ml) and brine (50 ml). Organic phase was dried (MgSO.sub.4),
evaporated, separated on a column with ethyl acetate-MeOH mixture
4:1, fractions collected to give
4-(benzylamino)-1,1-dimethoxybutan-2-ol (3.55 g, 14.83 mmol, 74.2%
yield), colorless oil.
(d)
N-Benzyl-N-(3-hydroxy-4,4-dimethoxybutyl)-2-nitrobenzenesulfonamide
(without isolation of 4-(benzylamino)-1,1-dimethoxybutan-2-ol)
[0172] To a solution of
(E)-4-(benzylamino)-1,1-dimethoxybut-3-en-2-one (1.176 g, 5 mmol)
in a mixture of 2-Propanol (12.5 ml) and Water (1.200 ml) was added
sodium borohydride (0.757 g, 20.00 mmol) in portions, the mixture
was stirred for 7 hours. Quenched with 5N HCl to pH 7 (approx 2.5
ml), pH adjusted to 8-9 with 5N NaOH, diluted with MTBE (25 ml) and
brine (15 ml). Organic phase was separated, triethylamine (0.767
ml, 5.50 mmol) was added with ice-cooling followed by
2-nitrobenzene-1-sulfonyl chloride (1.108 g, 5.00 mmol). The
mixture was left at 0-5.degree. C. (fridge) overnight. Washed with
water, dried, evaporated to dryness, the residue applied on a
column, eluted with petroleum ether-ethyl acetate mixture 1:1,
fractions collected to give
N-benzyl-N-(3-hydroxy-4,4-dimethoxybutyl)-2-nitrobenzenesulfonamide
(1.9 g, 4.48 mmol, 90% yield), yellow oil.
(e) N-Benzyl-N-(4-hydroxy-3-oxobutyl)-2-nitrobenzenesulfonamide
[0173] To a solution of
N-benzyl-N-(3-hydroxy-4,4-dimethoxybutyl)-2-nitrobenzenesulfonamide
(0.212 g, 0.5 mmol) in 1-Propanol (1.5 ml) was added 37%
hydrochloric acid (0.104 ml, 1.250 mmol) and the mixture was
stirred at 90.degree. C. in a weaton vial. Cooled, evaporated to
dryness under vacuum, applied on a column in petroleum ether-ethyl
acetate mixture 1:1, eluted with the same system. Fractions
collected to give
N-benzyl-N-(4-hydroxy-3-oxobutyl)-2-nitrobenzenesulfonamide (0.085
g, 0.225 mmol, 44.9% yield), yellowish oil.
Example 19
N-Benzyl-N-(4-hydroxy-3-oxobutyl)-2-nitrobenzenesulfonamide
(Compound I)
##STR00037##
[0174] 1-Hydroxybut-3-en-2-one
[0175] Prepared from but-2-yne-1,4-diol (Justus Liebigs Annalen der
Chemie, 1955, v. 596, p. 38-78). Pd, Cu and Zn catalysts were used
as alternatives to the Hg catalyst.
N-Benzyl-N-(4-hydroxy-3-oxobutyl)-2-nitrobenzenesulfonamide
[0176] To a solution of benzylamine (10.92 ml, 100 mmol) in DCM
(150 ml) was added triethylamine (13.67 ml, 100 mmol) followed by a
solution of 2-nitrobenzene-1-sulfonyl chloride (22.16 g, 100 mmol)
in DCM (70 ml) at 5-10.degree. C. with stirring. The mixture was
stirred for 1 hour, stirring continued for 1 hour, washed with
water, brine, most of DCM removed under reduced pressure. Ethyl
acetate (150 ml) was added, another 25-30 ml distilled off under
reduced pressure. To the resulting solution potassium tert-butoxide
(0.561 g, 5.00 mmol) was added followed by 1-hydroxybut-3-en-2-one
(9.47 g, 110 mmol) with stirring in one portion at 20-25.degree. C.
The mixture was stirred for 1 hour at 20-25.degree. C., diluted
with heptane (70 ml), washed with brine and 1N HCl (5 ml), organic
phase was dried (MgSO.sub.4), evaporated to dryness under reduced
pressure. The resulting oil was purified on a column with ethyl
acetate-petroleum ether mixture as eluent. Fractions containing the
wanted product were collected and evaporated to dryness under
reduced pressure to give
N-benzyl-2-nitro-N-(4-hydroxy-3-oxobutyl)benzenesulfonamide (29.1
g, 77 mmol, 77% yield).
Example 20
N-benzyl-N-(4-hydroxy-3-oxobutyl)-ethyl methanoate (Compound I with
Alternative Protecting Group--Ethyl Ethanoate Instead of Ns)
##STR00038##
[0178] The steps were carried out as follows.
(a) Ethyl benzyl(4-hydroxybut-2-ynyl)carbamate
[0179] A mixture of benzylamine (2.185 ml, 20.00 mmol) and
4-chlorobut-2-yn-1-ol (1.045 g, 10.00 mmol) was stirred in EtOH (20
ml) for 1 hour under reflux. The mixture was cooled, evaporated to
dryness under vacuum, the semi-solid residue was taken up into
acetone (50 ml), the insoluble material was filtered off
(benzylamine hydrochloride), the filtrate evaporated to dryness.
The residue was dissolved in 96% EtOH (20 ml), triethylamine (4.18
ml, 30.0 mmol) was added followed by ethyl chloroformate (2.113 ml,
22.00 mmol) dropwise with ice-cooling and stirring. Allowed to warm
up naturally with stirring during 1 hour, evaporated to dryness
under vacuum, the residue was distributed between DCM (50 ml) and
1N HCl (25 ml). Organic phase was dried, evaporated to dryness,
applied on a column, eluted with petroleum ether-ethyl acetate
mixture 4:1=>2:1, fractions collected to give 2 g of less polar
yellowish oil and 0.34 g of more polar oil. Less polar fraction was
dissolved in ether, acidified with HCl/EtOH, diluted with
(petroleum ether) PE (approx 1:1). Liquid was decanted from the
separated oil and evaporated to dryness to give 1.6 g of oil. The
oil was dissolved in MeOH (20 ml), 5N sodium hydroxide (2.000 ml,
10.00 mmol) added, stirred at 20-25.degree. C. for 16 hours.
Acidified to pH 6 with concentrated HCl, evaporated to dryness,
taken up into DCM, organic phase dried, combined with more polar
oil, separated on a column with petroleum ether-ethyl acetate
mixture 4:1=>2:1. Fractions were collected under HPLC-MS control
to give ethyl benzyl(4-hydroxybut-2-ynyl)carbamate (0.71 g, 2.87
mmol, 28.7% yield).
[0180] .sup.1H NMR, 400 MHz, 20.degree. C., CDCl.sub.3) .delta.:
7.40-7.20 (5H, m), 4.59 (2H, s br), 4.24 (2H, m br), 4.22 (2H, t,
J=7.1 Hz), 4.1-3.95 (2H, m br), 2.05, 1.95 (1H, 2 s br), 1.29 (3H,
t br, J=7.0 Hz); .sup.13C NMR (100 MHz, 20.degree. C., CDC.sub.3)
.delta.: 156.1, 137, 128.5, 128.2, 127.7, 127.5, 82.1, 81.9, 80.8,
62, 51, 49.3, 35.8, 35.4, 14.6.
(b) Ethyl benzyl(4-hydroxy-3-oxobutyl)carbamate
[0181] A mixture of ethyl benzyl(4-hydroxybut-2-ynyl)carbamate
(0.05 g, 0.202 mmol), mercury(II) acetate (6.44 mg, 0.020 mmol) and
boron trifluoride etherate (5.12 .mu.l, 0.040 mmol) in Acetonitrile
(0.5 ml) and Water (0.250 ml) stirred at 90.degree. C. in wheaton
vial for 30 min. By HPLC-MS the main peak corresponds to expected
product.
Example 21
(R)-6,8-difluorochroman-3-amine L-Tartrate salt (Compound JT')
[0182] The vessel was charged with (R)-methyl
6,8-difluorochroman-3-ylcarbamate (1.0 wt) and methanol (12.66
vol.), the content temperature was adjusted to 65.degree. C. with
stirring. A solution of potassium hydroxide (2.76 wt) in water
(4.15 vol.) was transferred to the vessel while maintaining
65.degree. C. and the mixture was stirred for 24 hours. The content
was adjusted to 35.degree. C., water (5.6 vol.) was charged and the
vessel was set up for atmospheric distillation. The content was
distilled off at 70.degree. C. internal temperature and 80.degree.
C. in doubled jacket until a residual volume reached 8-10 vol. The
content adjusted to 30.degree. C., dichloromethane (6.5 vol.) was
charged while cooling the content temperature to 20/25.degree. C.
Stirred for 15 min, settled for 15 min, the lower organic phase was
separated. Dichloromethane (3.0 vol.) was charged, the mixture
stirred for 15 min, settled for 15 min, the lower organic phase was
separated. Combined organic phase was washed twice with brine and
transferred to a vessel set up for vacuum distillation. The vessel
was charged with ethanol (20.0 vol.), 4.3 vol. of distillate was
distilled off. The vessel was set up for atmospheric distillation;
content of the vessel was distilled off at 65/75.degree. C.
internal temperature and 90.degree. C. in doubled jacket until
vessel volume was 20.0 vol. and then distilled at constant volume
by the addition of ethanol until refractive index showed no
dichloromethane was present. A solution of L-tartaric acid (0.647
wt, 1.108 eq) in water (3.0 vol.) was prepared and adjusted to
70.degree. C. The solution was added slowly to previously obtained
ethanolic solution at 75.degree. C. The mixture stirred at
75.degree. C. for 5 hours then cooled to 0.degree. C. at 10.degree.
C./hour. The content was stirred at 0.degree. C. for 12 hours,
ethanol (2.5 vol.) was charged and the temperature was adjusted to
0.degree. C. The content of the vessel was transfer to a filter.
The filter cake was washed with ethanol (5.0 vol. and 2.5 vol.) and
dried under vacuum at 45.degree. C. Yield of
(R)-6,8-difluorochroman-3-amine L-Tartrate salt 90% of theory.
[0183] .sup.1H NMR (400 MHz, DMSO, 20.degree. C.) .delta.: 7.14
(1H, m, J=3.0, 8.9 and 11.5), 6.92 (1H, d br, J=9.3), 4.24 (1H, dd,
J=2.4 and 11.3), 4.17 (1H, dd, J=5.6 and 11.2), 4.02 (2H, s), 3.72
(1H, m), 3.17 (1H, dd, J=5.7 and 17.5), 2.84 (1H, dd, J=5.3 and
17.5); .sup.13C NMR (100 MHz, DMSO, 20.degree. C.) .delta.: 174.6,
155.1 (dd, J=11.5 and J=239.0), 150.3 (dd, J=13.0 and 246.0), 138.5
(dd, J=3.3 and 11.5), 122.9 (dd, J=2.5 and 9.5), 111.3 (dd, J=3.5
and 23.0), 102.9 (dd, J=22.5 and 27.5), 72.1, 66.7, 42.7, 28.7.
[0184] It will be appreciated that the invention described above
may be modified within the scope of the attached claims.
* * * * *